Protein kinases are enzymes that covalently modify proteins by attaching phosphate groups (from ATP) to serine, threonine, and/or tyrosine residues. In so doing, the functional properties of the protein kinase's substrates are modified. Protein kinases transduce signals from the cell membrane into the interior of the cell. Such signals include not only those arising from ligand-receptor interactions but also environmental perturbations when the membrane undergoes mechanical deformation (i.e., cell stretch or shear stress). Ultimately, the activation of signaling pathways that use protein kinases often culminate in the reprogramming of gene expression through the direct regulation of transcription factors or through the regulation of mRNA stability or protein translation. Protein kinases regulate most aspects of normal cellular function.
Many signal transduction pathways involved in the control of cell proliferation and differentiation originate with transmembrane receptors containing cytoplasmic protein kinase domains. For instance, there are many kinds of cytokine and growth factor receptors that belong to different receptor families. Most of these receptors function as: (1) receptor tyrosine kinase and tyrosine-kinase-associated receptor (see, for example, Fanti et al. (1993) Annu. Rev. Biochem, 62:453); (2) receptors serine/threonine kinase (for example, Josso and di Clemente, (1997) Curr Opin Genet Dev., 7:371-7; Dijke et al. (1996), Curr Opin Cell Biol., 8(2):139-45); or (3) G-protein linked receptors (Piper and Zeuzem (2004) Curr Pharm Des., 10(28):3539-45; Presland (2004) Biochem Soc Trans., 32(Pt 5):888-91). Following binding with an extracellular ligand and activation, the receptors trigger different cascade of intracellular protein phosphorylation to transduction signals, thereby altering the cell's pattern of gene expression and leading to biological effects.
The pathophysiological dysfunction of protein kinase signaling pathways underlies the molecular basis of many cancers and of several manifestations of cardiovascular disease, such as hypertrophy and other types of left ventricular remodeling, ischemia/reperfusion injury, angiogenesis, and atherogenesis. Because of the important roles the protein kinases play, they have emerged as crucial targets for a variety of diagnostic and therapeutic indications, including, cancer, inflammatory disorders, autoimmune diseases (e.g., diabetes), cardiovascular diseases, and neurological disorders.